Abnormalities of Body-Fat Distribution

July 2006; updated July 2007

Chapter Contents

Background

Subjective

Objective

Assessment

Plan

Patient Education

References

Background

Body-fat abnormalities are a recognized complication of antiretroviral therapy (ART). These include central fat accumulation, subcutaneous fat atrophy, and the development of lipomas. Taken together, these abnormalities in fat distribution and body shape have been noted in up to 40-50% of patients treated with ART. The etiology of these changes in body habitus is not well understood, but research to date suggests that it is multifactorial, with components related to specific antiretroviral (ARV) medications, HIV-related immune depletion and immune recovery, hormonal influences, individual genetic predispositions, and non-HIV-related factors such as diet and obesity. In fact, lipodystrophy probably is not a single syndrome, but rather several separate but interrelated clinical presentations.

Lipodystrophy may present as isolated fat accumulation (lipoaccumulation), fat wasting (lipoatrophy), or a combination of both. The most common morphologic changes seen in fat accumulation are an enlarged abdomen from central or visceral fat accumulation, breast enlargement (gynecomastia), and development of a dorsocervical fat pad ("buffalo hump"). Lipoatrophy is seen most commonly as the loss of subcutaneous fat in the face, arms, legs, and buttocks. Lipoatrophy differs from the generalized wasting seen in advanced AIDS, because lean cell mass generally is preserved.

Severe lipoaccumulation can cause discomfort and, in some cases, impairment of breathing or other bodily functions. It also may be associated with other metabolic abnormalities, including dyslipidemia and the metabolic syndrome. Both lipoaccumulation and lipoatrophy can be disfiguring, can damage self-image and quality of life, and can negatively influence ARV adherence.

Research into the causes and manifestations of lipodystrophy has yielded varying results, in part because there is no standard clinical case definition of lipodystrophy. The prevalence of and risk factors for lipodystrophy are not well understood. The condition seems to develop more frequently in patients who are older and have longer exposure to ART. In some studies, lipodystrophy has been associated with lower nadir CD4 count as well as with sex (central lipoaccumulation may be more common in women). It has been associated with protease inhibitors (PIs) and with nucleoside reverse transcriptase inhibitors (NRTIs), but does not appear to be associated with nonnucleoside reverse transcriptase inhibitors (NNRTIs). However, it may develop in patients who have never received PIs, and occasionally in ARV-naive individuals. PIs appear to be associated more commonly with fat accumulation, whereas NRTIs, most notably stavudine, are associated with lipoatrophy.

S: Subjective

The patient may report any of the following: abdominal fat accumulation with change in waist size, increased neck size, "buffalo hump," and enlarged breasts; women may note an increase in bra size. The patient also may report sunken cheeks, temporal wasting, decreased arm or leg circumference, prominence of veins in the arms or legs, buttock flattening, and even pain in walking because of atrophy of fat padding around the soles of the feet. The patient may volunteer that these changes are causing emotional distress.

Inquire about CD4 nadir, ARV medication history, duration of and response to each regimen, and recent medication adherence. Ask about past medical and family history, specifically regarding hyperlipidemia, diabetes or insulin resistance, other metabolic disorders, and cardiovascular disease. Elicit the patient's emotional responses to the body shape changes.

O: Objective

Compare past and current weights. Calculate body mass index. Measure and document waist and hip circumferences; check waist-to-hip ratio. An abdominal circumference >102 cm (39 inches) in men and >88 cm (35 inches) in women is the clinical definition of abdominal obesity and is associated with the metabolic syndrome. Waist-to-hip ratios >0.95 in men and >0.85 in women are associated with an increased risk of coronary heart disease.

Examine the head, neck, back, breasts, and abdomen for fat accumulation, especially looking for dorsocervical fat pad and facial, neck, or breast enlargement. Examine the face and extremities for subcutaneous fat loss (eg, in the cheeks, temples, limbs, and buttocks).

Review laboratory history (glucose, lipid panel), to identify other metabolic disorders. (See chapters Dyslipidemia and Insulin Resistance and Hyperglycemia on ART .)

A: Assessment

No uniform standard criteria are available for defining or grading lipodystrophy in clinical practice. Clinicians must base their assessment on physical examination (for characteristic body-shape changes) and lipodystrophy-associated symptoms and psychological consequences.

In research settings, modalities such as dual-energy x-ray absorptiometry (DEXA), computed tomography (CT), and magnetic resonance imaging (MRI) have been used to characterize lipodystrophy. Anthropometric measurements may be made in the clinic by trained personnel (eg, nutritionists), but do not measure visceral fat directly. Although measurements such as waist circumference cannot be used to assess lipodystrophy, they have been validated (in non-HIV-infected individuals) as an assessment of cardiovascular risk. Bioelectrical impedance analysis (BIA) does not measure regional body composition and thus is not used to measure abnormal body-fat changes.

P: Plan

Laboratory

Check for other metabolic abnormalities associated with the use of ART, such as dyslipidemia and impaired glucose metabolism. See chapters Dyslipidemia and Insulin Resistance and Hyperglycemia on ART for further information about workup and treatment.

Evaluate the effect of body-shape changes on the patient's self-esteem, medication adherence, and interpersonal relationships. Refer the patient for psychological or adherence support and counseling, if indicated. If the patient is distressed enough to consider discontinuing or interrupting ART, review with the patient any gains he or she has made on ART and discuss treatment options (see below). In some cases the patient may insist on discontinuing ARV medications; in this situation, carefully review the risks and benefits of treatment interruption, as well as the alternatives to discontinuing treatment.

Treatment

Consistently effective treatments for lipodystrophy have yet to be identified. In general, patients with marked or severe lipodystrophy have shown poor or inconsistent responses to interventions. The best approaches to lipodystrophy are prevention and early intervention.

Clinicians can help to prevent lipodystrophy by avoiding, whenever possible, ARV agents known to confer a greater risk of this disorder (particularly stavudine). All patients who take ARVs should be monitored carefully for the development of lipodystrophy. If lipodystrophy is noticed, intervention should be initiated, if possible.

The optimal management of lipodystrophy is not known, although the following approaches can be considered. Also consider referring the patient to clinical studies of lipodystrophy treatment.

Drug Substitutions

Avoiding thymidine analogue NRTIs, particularly stavudine, and avoiding the NRTI combination stavudine + didanosine have been shown to reduce the risk of lipoatrophy. In patients with lipoatrophy, modest long-term improvement has been demonstrated after switching from thymidine analogues (stavudine and zidovudine) to nonthymidine analogues (such as abacavir or tenofovir) or to NRTI-sparing regimens. Before switching therapies, carefully assess the potential risk to the patient's long-term HIV management.

Nonpharmacologic Measures

Diet

The effects of diet on lipodystrophy have not been evaluated thoroughly. If overall weight reduction is needed, recommend dietary changes and exercise. Avoid rapid weight loss plans, as lean body mass is often lost disproportionately. Refer to a dietitian, to help the patient decrease his or her intake of saturated fat, simple sugars, and alcohol.

Exercise

Regular, vigorous cardiovascular exercise may help control central fat accumulation, whereas muscle-building (strength training) will improve the ratio between fat and muscle. Some studies of exercise have shown a reduction in visceral fat accumulation with minimal or no changes in peripheral lipoatrophy. Moderate aerobic exercise should be encouraged in all patients.

Pharmacologic Measures

Recombinant Human Growth Hormone

Treatment with recombinant human growth hormone (rHGH), 3-6 mg/d for 12 weeks followed by maintenance therapy with lower doses of 1-2 mg/d, has been shown to reduce visceral fat with minimal impact on peripheral fat wasting. However, the high cost of rHGH, the high rate of adverse effects (including insulin resistance), and the frequent recurrence of morphologic abnormalities once rHGH is discontinued have resulted in a limited role for this treatment.

Insulin-Sensitizing Agents

In diabetic and non-HIV lipodystrophy, treatment with thiazolidinediones may decrease visceral fat, increase peripheral fat, and improve glycemic control. Unfortunately, studies of rosiglitazone as treatment for lipoatrophy in HIV-infected patients have shown mixed results. Some small studies have reported improvement in peripheral fat loss; however, a larger, 48-week randomized trial of rosiglitazone in HIV-infected patients with lipoatrophy found no improvement in fat mass. Therefore, rosiglitazone cannot be recommended currently for the treatment of lipoatrophy.

Metformin has been somewhat effective in treating lipoaccumulation in patients with insulin resistance, but may cause worsening of lipoatrophy. Metformin should not be given to patients with an elevated risk of lactic acidosis.

Studies of insulin-sensitizing agents continue.

Plastic and Reconstructive Surgery

Various techniques have been investigated, but generally have limited applicability and efficacy. These include liposuction and breast reduction for lipoaccumulation, and cheek implants and autologous fat transfer for facial lipoatrophy. Poly-L-lactic acid (Sculptra, New-Fill) is approved by the U.S. Food and Drug Administration as a treatment for facial lipoatrophy. This injectable material has shown to good cosmetic results, at least in the short term.

Although plastic surgery can help some people with lipodystrophy, the treatments are expensive, may need to be repeated, and usually are not covered by private or public-payer sources. In some cases, they may be only a temporary solution, because abnormalities may reappear after treatment.

Patient Education

• Instruct patients who are receiving ARV medications to inform their health care providers if they notice changes in the shape or appearance of their bodies.
• Review the importance and benefits of ART and assess adherence to the regimen.
• For patients with lipoaccumulation, recommend aerobic and resistance exercise to build muscle and reduce fat. Assess resources in your area for safe muscle-strengthening possibilities.
• If weight reduction is needed, refer to a dietitian for consultation. Remind the patient that quick weight loss diets may result in excessive muscle loss.

References

• Carr A, Workman C, Carey D, et al. No effect of rosiglitazone for treatment of HIV-1 lipoatrophy: randomised, double-blind, placebo-controlled trial . Lancet. 2004 Feb 7;363(9407):429-38.
• Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial . JAMA. 2004 Jul 14;292(2):191-201.
• Martin A, Smith DE, Carr A, et al. Reversibility of lipoatrophy in HIV-infected patients 2 years after switching from a thymidine analogue to abacavir: the MITOX Extension Study . AIDS. 2004 Apr 30;18(7):1029-36.
• Norris A, Dreher HM. Lipodystrophy syndrome: the morphologic and metabolic effects of antiretroviral therapy in HIV infection . J Assoc Nurses AIDS Care. 2004 Nov-Dec;15(6):46-64.
• Schambelan M, Benson CA, Carr A, et al. Management of metabolic complications associated with antiretroviral therapy for HIV-1 infection: recommendations of an International AIDS Society-USA panel . J Acquir Immune Defic Syndr. 2002 Nov 1;31(3):257-75.
• U.S. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents . October 10, 2006. Available online at aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?GuidelineID=7. Accessed July 3, 2007.